antiviral agents Flashcards
acyclovir and derivatives are used to treat…
herpes virus
hsv1
hsv2
vzv
1 - oral herpes and herpes keratitis
2 - genital herpes
vzv - chicken pox and shingles
acyclovir
structure and mechanism of action
guanosine analog with an acyclical sugar
used to treat herpes viruses
• Acyclovir does NOT cure herpes infection; it suppresses and shortens outbreaks
- Mechanism of action = chain termination
- REQUIRES viral thymidine kinase enzyme for activation from pro-drug to active form (host enzymes will not do this primary phosphorylation)
gmp –> gtp
NRTIs used to treat HIV vs acyclovir for HSV
• REQUIRES viral thymidine kinase enzyme for activation from pro-drug to active form (host enzymes will not do this primary phosphorylation)
o In contrast, NRTIs used to treat HIV use host-encoded nucleoside kinases for activation
valaciclovir
- A valine ester of acyclovir
* Activated in liver achieves higher serum levels due to greater bioavailability
NRTIs
NRTIs (nucleoside reverse transcriptase inhibitors) = ZEAL (zidovudine, emtricitabine, abacavir, lamivudine) + DT (didanosine, tenofovir)
all are prodrugs that require cellular kinases (phosphorylation) for activation (thymidine kinase)
zidovudine (AZT)
NRTI
mechanism: 1) competitive inhibition of HIV reverse transcriptase(RT) and 2)premature chain termination
Decreases HIV progression
o Side effects: macrocytic anemia and neutropenia; potential to induce lactic acidosis (DNA pol gamma)
is zidovudine safe for pregnanct?
yes
reduces transmission of HIV to offspring
emtricitabine
NRTI, used to treat HIV and HBV
fluorinated analog of lamivudine with longer half life
abacavir
NRTI with hypersensitivity reactions
hepatomegaly (especially in HLA-B5701 patients; only give after you genotype the patient
what are the 6 NRTIs?
what do they require to work?
what are they used to treat?
zidovudine emtricitabine abacavir lamivudine didanosine tenofovir ZEALDT
require thymidine kinase for activation
treat HIV and hepB
what does thymidine kinase do for NRTIs
phosphorylates them to turn them from prodrugs to activated drugs
lamivudine (3TC)
NRTI; used for HIV and hepB
LOW side effects:) great for pregnancy use
didanosine
NRTI, with risk of pancreatitis, peripheral neuropathy, and severe liver problems
tenofovir
NRTI that is a nucleotide analog that competitively inhibits HIV RT and causes chain termination; used for HBV and HIV
a nucleoside phosphonate that is converted to di and triphosphate in resting cells –> doesnt require initial phosphorylation for activation);
watch for renal toxicity
NNRTIs
non-nucleoside RT inhibitors
(names contain -vir-) nevirapine, rilpivirine, etravirine, efavirenz, delaviridine =RNEED
do not require phosphorylation to be active
do not compete with NRTIs or nucleotides for RT binding –> no cross resistance since they work at different sites!
but high potential for drug interactions –> they inhibit and induce cyp3a4
unlike NRTIs, NNRTIs….
do not require phosphorylation for activation
can NRTIs be used with NNRTIs?
yes
they do not compete with NRTIs or nucelotides for RT binding –> no cross-resistance since they are working at different sites
why is there high potential for drug interactions with NNRTIs?
they all inhibit or induce cyp3a4
nevirapine
NNRTI, for HIV
prophylaxis for pregnant women
can cause stevens johnson syndrome
rilpivirine
very high cross resistance, cannot use with other NNRTIs
etravirine
good for patients who are resistant to other NNRTIs
efavirenz
NNRTI; NOT TO BE USED with pregnancy –> fetal defects
delaviridine
NNRTI
inhibits cyp3a4 and causes skin rashes
which nnrti should be used with pregnancy? not be used with pregnancy?
P- nevirapine
not with P - efavirenz
if an HIV patient is resistant to most NNRTIs, which should be used?
etravirine
many HIV patients are also co-infected with what?
hep B (HBV)
HIV vs HBV
HIV is a retro virus and HBV is a DNA virus
both use reverse transcriptase
what is HBV?
a DNA virus that can be transmitted sexually or through infected blood
causes chronic liver disease (hepatitis and cirrhosis)
there is a vaccine
best two NRTIs that treat both HIV and HBV
lamivudine
tenofovir
1st line drugs for HBV
all DNA polymerase/reverse transcriptase inhibitors
=HBV LATTE
lamivudine adefovir (nucleotide RTI) tenofovir (nucleotide RTI) telbivudine (thymidine analog) entecavir (guanosine analog)
mechanism for HIV cell attachment
HIV infects CD4+ helper T cells, macrophages, and dendritic cells.
GP120 binds CD4 receptor and CCR5 receptor (chemokine co-receptor)
binding of gp120 causes conformational changes that enables gp41 to fuse virus and host cell membrane –> 2 gp41 molecules pull the virion into the cell!
2 drugs that are HIV virus binding inhibitors
maraviroc
enfuvirtide
maraviroc
HIV drug that inhibits binding of gp120 to CCR5 (chemokine receptor 5)
will NOT work if the viral strain uses the CXCR4 receptor instead of CCR5 (so genotype the virus first!)
enfuvirtide
HIV drug that locks gp41 in the extended conformation –> inhibits fusion of virus and host cell
provirus and integrase
a provirus is viral DNA that is integrated into the host chromosomal DNA by the enzyme integrase
INSTIs
integrase strand transfer inhibitors
oral HIV drugs that inhibit integrase from integrating viral DNA into chromosomal host DNA
raltegravir
elvitegravir
dolutegravir
any drug that ends with -gravir does what?
inhibits integrase; treats HIV
raltegravir
elvitegravir
dolutegravir
protease involvement in HIV virus?
during maturation, the protease enzyme cleaves polyprotein to Gag proteins, resulting in new infectious virions.
• Without Protease, viral particles would be non-infectious; it is important for processing them into functional virions
• HIV protease (PR), integrase, RNase H, and reverse transcriptase (RT) are initially expressed as a Gag-Pol fusion protein
o In maturation, HIV protease cleaves the gag-pol polypeptide to separate the protease, RT, RNase, and integrase
HIV protease inhibitors
all end in -avir
do not require any modification for activation
use in combination (ritonavir + darunavir, lopinavir, saquinavir, or tipranavir)
always w ritonavir since ritonavir increases the concentration of other protease inhbitors (synergistic)
HIV protease inhibitor with lower incidence of lipodystrophies?
atazanavir
HIV protease inhibitor combo recommended with pregnancy
lopinavir
ritonavir
side effects of using HIV protease inhibitors
redistributed body fat (central obesity, dorsocervical fat (buffalo hump), facial wasting) (LIPODYSTROPHIES)
–increased LDL, decreased HDL, increased triglycerides hyperglycemia, insulin resistance
PrEP
preexposure prophylaxis for HIV in high risk groups
truvada = emtricitabine + tenofovir
what is hepatitis C?
parenteral transmission; risk factors = exposure to mucosal surfaces, sharing contaminated needles and unprotected sex with infected partner, transfusion
many infected people develop viral persistence
causes liver transplantation and Hepatocellular carcinoma.
treatment for hepC
triple therapy
boceprevir or telapravir +
Peg-IFN +
ribavirin
4 drugs for hepC
interferons
ribavirin
sofosbuvir
Hcv protease inhibitors (-previr)
interferons as hcv drug
Interferon alphas have general antiviral activity (hepatitis B and C)
Most effective against C when used in combination with ribavirin
reduce development of chronic infections if taken during acute phase
Pegylated forms (Peg-IFN) have improved pharmacokinetic properties
side effects of interferons in HCV treatments
SIDE EFFECTS: flulike - fever, headache, muscle ache, chills Can affect compliance.
ribavirin
Broad-spectrum antiviral drug; used in combination with IFN alpha for HCV.
Inhibits purine biosynthesis, interferes with RNA metabolism needed for viral replication. Requires kinase activation.
treatment for RSV (respriatory syncytial virus?
aerosolized ribavirin
HCV protease inhibitors
boceprevir, telaprevir, simeprevir
used in combination therapy with other HCV
Used with ribavirin and INFα
sofosbuvir
HCV treatment drug
—-Inhibits HCV RNA synthesis; Substrate of NS5B polymerase
Pro drug (requires kinases for activation via phosphorylation)
pan-genotypic antiviral–>approved for gentotypes 1-4
